[Systemic lupus erythematosus associated macrophage activation syndrome with neuropsychiatric symptoms: A report of 2 cases].

Systemic lupus erythematosus (SLE) associated macrophage activation syndrome (MAS) is clinically severe, with a high mortality rate and rare neuropsychiatric symptoms. In the course of diagnosis and treatment, it is necessary to actively determine whether the neuropsychiatric symptoms in patients are caused by neuropsychiatric systemic lupus erythematosus (NPSLE) or macrophage activation syndrome. This paper retrospectively analyzed the clinical data of 2 cases of SLE associated MAS with neuropsychiatric lesions, Case 1: A 30-year-old female had obvious alopecia in 2019, accompanied by emaciation, fatigue and dry mouth. In March 2021, she felt weak legs and fell down, followed by fever and chills without obvious causes. After completing relevant examinations, she was diagnosed with SLE and given symptomatic treatments such as hormones and anti-infection, but the patient still had fever. The relevant examinations showed moderate anemia, elevated ferritin, elevated triglycerides, decreased NK cell activity, and a perforin positivity rate of 4.27%, which led to the diagnosis of "pre-hemophagocytic syndrome (HPS)". In May 2021, the patient showed mental trance and babble, and was diagnosed with "SLE-associated MAS"after completing relevant examinations. After treatment with methylprednisolone, anti-infection and psychotropic drugs, the patient's temperature was normal and mental symptoms improved. Case 2: A 30-year-old female patient developed butterfly erythema on both sides of the nose on her face and several erythema on her neck in June 2019, accompanied by alopecia, oral ulcers, and fever. She was diagnosed with "SLE" after completing relevant examinations, and her condition was relieved after treatment with methylprednisolone and human immunoglobulin. In October 2019, the patient showed apathy, no lethargy, and fever again, accompanied by dizziness and vomiting. The relevant examination indicated moderate anemia, decreased NK cell activity, elevated triglycerides, and elevated ferritin. The patient was considered to be diagnosed with "SLE, NPSLE, and SLE-associated MAS". After treatment with hormones, human immunoglobulin, anti-infection, rituximab (Mabthera), the patient's condition improved and was discharged from the hospital. After discharge, the patient regularly took methylprednisolone tablets (Medrol), and her psychiatric symptoms were still intermittent. In November 2019, she developed symptoms of fever, mania, and delirium, and later turned to an apathetic state, and was given methylprednisolone intravenous drip and olanzapine tablets (Zyprexa) orally. After the mental symptoms improved, she was treated with rituximab (Mabthera). Later, due to repeated infections, she was replaced with Belizumab (Benlysta), and she was recovered from her psychiatric anomalies in March 2021. Through the analysis of clinical symptoms, imaging examination, laboratory examination, treatment course and effect, it is speculated that the neuropsychiatric symptoms of case 1 are more likely to be caused by MAS, and that of case 2 is more likely to be caused by SLE. At present, there is no direct laboratory basis for the identification of the two neuropsychiatric symptoms. The etiology of neuropsychiatric symptoms can be determined by clinical manifestations, imaging manifestations, cerebrospinal fluid detection, and the patient's response to treatment. Early diagnosis is of great significance for guiding clinical treatment, monitoring the condition and judging the prognosis. The good prognosis of the two cases in this paper is closely related to the early diagnosis, treatment and intervention of the disease.

The effects of Smad6 via small RNA pathways on the ischemic injury in PC12 cells.

BACKGROUND: Though we have reported the neuroprotective effect of exogenous ActA on oxygen-glucose deprivation (OGD) injury, the endogenous role of Smad6 remains not well understood. Smad6 is an important regulator of the ActA/smads signaling via a negative feedback circuit. METHODS: In this study, nerve growth factor (NGF) and OGD were used to stimulate (rat adrenal pheochromocytoma) PC12 cells converting them into neurons to establish an ischemia in vitro model. Combined with the small interfering technology of Smad6 and FCM, Hoechst and Western blot were used to identify the apoptosis rate. The effect of silencing of Smad6 with siRNA was observed. RESULTS: These results showed that the apoptosis rate was 21.54% by 16-h OGD. For the combined Smad6-siRNA, the apoptosis rate was 10.55%. CONCLUSIONS: The expression of procaspase-3 protein was increased by Smad6-siRNA.The expression of ActA and p300 was also increased. The apoptosis rate was decreased in the ischemic injury with Smad6-siRNA. At the same time, it provided a reference to study the mechanism of Smad6 and its signaling in response to the acute ischemic damage.

Endogenous protection derived from activin A/Smads transduction loop stimulated via ischemic injury in PC12 cells.

Activin A (ActA), a member of transforming growth factor-beta (TGF-b) super- family, affects many cellular processes, including ischemic stroke. Though the neuroprotective effects of exogenous ActA on oxygen-glucose deprivation (OGD) injury have already been reported by us, the endogenous role of ActA remains poorly understood. To further define the role and mechanism of endogenous ActA and its signaling in response to acute ischemic damage, we used an OGD model in PC12 cells to simulate ischemic injury on neurons in vitro. Cells were pre-treated by monoclonal antibody against activin receptor type IIA (ActRII-Ab). We found that ActRII-Ab augments ischemic injury in PC12 cells. Further, the extracellular secretion of ActA as well as phosphorylation of smad3 in PC12 cells was also up-regulated by OGD, but suppressed by ActRII-Ab. Taken together, our results show that ActRII-Ab may augment ischemic injury via blocking of transmembrane signal transduction of ActA, which confirmed the existence of endogenous neuroprotective effects derived from the ActA/Smads pathway. ActRIIA plays an important role in transferring neuronal protective signals inside. It is highly possible that ActA transmembrance signaling is a part of the positive feed-back loop for extracellular ActA secretion.

Neuroprotective effects of exogenous activin A on oxygen-glucose deprivation in PC12 cells.

Ischemic cerebrovascular disease is one of the most common causes of death in the World. Exogenous activin A (ActA) protects neurons against toxicity and plays a central role in regulating the brain's response to injury. In the present study, we investigated the mechanisms involved in the neuroprotective effects of ActA in a model of hypoxic-ischemic brain disease. We found that ActA could effectively increase the survival rate of PC12 cells and relieve oxygen-glucose deprivation (OGD) damage. To clarify the neuroprotective mechanisms of ActA, the effects of ActA on the ActA/Smad pathway and on the up-regulation of inducible nitric oxide synthase (NOS) and superoxide dismutase (SOD) were investigated using OGD in PC12 cells. The results showed that ActA could increase the expression of activin receptor IIA (ActRIIA), Smad3 and Smad4 and that 50 ng/mL and 100 ng/mL of ActA could reduce NO levels and increase SOD activity by 78.9% and 79.9%, respectively. These results suggested that the neuroprotective effects of ActA in ischemia could be related to the activation of the ActA/Smad signaling pathway and to its anti-oxidant activities.

Protective effect of Astragalus polysaccharides on ATP binding cassette transporter A1 in THP-1 derived foam cells exposed to tumor necrosis factor-alpha.

Astragalus polysaccharide (APS), the main extract from the traditional Chinese medicinal herb Astragalus membranaceus, has been reported to benefit the treatment of immune-inflammatory diseases and metabolic disorders. In atherosclerotic plaques, proinflammatory cytokines exert adverse effects on lipids thereby aggravating atherosclerosis. Recent evidence shows that tumor necrosis factor-alpha (TNF-alpha) can down-regulate the expression of ATP-binding cassette transporter A1 (ABCA1), which plays a vital role in reverse cholesterol transport and determines the process of atherosclerosis. In the present study, the effects of APS on ABCA1 expression, cholesterol effluent rate and total cholesterol content of THP-1 derived foam cells exposed to TNF-alpha were investigated. Compared with the foam cells exposed to TNF-alpha, ABCA1 expression was promoted in the presence of APS. Consequently the cholesterol effluent rate increased and the total cholesterol content decreased significantly. TNF-alpha could enhance the activity of nuclear factor-kappa B (NF-kappaB) in the foam cells. This effect could be attenuated by APS. These findings suggest that APS could protect ABCA1 against the lesion of TNF-alpha in THP-1 derived foam cells, which may contribute to its antiatherosclerotic properties.

Chlamydia pneumoniae induces macrophage-derived foam cell formation via PPAR alpha and PPAR gamma-dependent pathways.

In the presence of low density lipoprotein (LDL), Chlamydia pneumoniae induces macrophage-derived foam cell formation, a typical pathological feature of early atherosclerosis. However, its mechanism has not been fully understood. Peroxisome proliferator-activated receptors (PPARs) are key regulators of macrophage lipid metabolism. This study therefore investigated the role that PPAR alpha and PPAR gamma may play a role in C. pneumoniae-induced foam cell formation. Oil Red O staining and Lipid mass quantification showed that LDL-treated THP-1 macrophages infected with high doses of C. pneumoniae (5x10(5) and 1x10(6)IFU) resulted in the large accumulation of lipid droplets and markedly increased the ratio of intracellular cholesteryl ester (CE) to total cholesterol (TC) (>50%). The results of RT-PCR and Western blot indicated that C. pneumoniae infection dose-dependently suppressed the expression of PPAR alpha and PPAR gamma at mRNA and protein levels in LDL-treated THP-1 macrophages. PPAR alpha (fenofibrate) and PPAR gamma (rosiglitazone) agonists, inhibited the accumulation of intracellular CE by C. pneumoniae in a dose-dependent manner. Furthermore, C. pneumoniae-induced foam cell formation was significantly suppressed by higher doses of fenofibrate (20 and 50microM) and rosiglitazone (10 and 20microM). These results first reveal that C. pneumoniae induces foam cell formation via PPAR alpha and PPAR gamma-dependent pathway, which may contribute to its pro-atherogenic properties.

[Chlamydia pneumoniae induces THP-1-derived foam cell formation by up-regulating the expression of acyl-coenzyme A: cholesterol acyltransferase 1].

OBJECTIVE: To investigate the expression changes of acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) on Chlamydia pneumoniae (C.pn) induced foam cell formation. METHODS: Human monocytic cell line (THP-1) was induced into macrophages by 160 nmol/L phorbol myristate acetate (PMA) for 48 h, and were randomly allocated into four groups: negative control group (50 microg/ml LDL for 48 h); positive control group (50 microg/ml ox-LDL for 48 h); C.pn infection group (50 microg/ml LDL plus 1 x 10(5), 4 x 10(5), 5 x 10(5) and 1 x 10(6) IFU C.pn for 48 h or 1 x 10(6) IFU C.pn for 0, 24, 48 and 72 h); ACAT inhibitor 58-035 plus C.pn infection group (1, 5, 10 microg/ml ACAT inhibitor 58-035 pretreatment for 1 h, 50 microg/ml LDL and 1 x 10(6) IFU C.pn for 48 h). The mRNA and protein expressions of ACAT1 were determined by RT-PCR and Western blot, respectively. Lipid droplets in cytoplasm were observed by oil red O staining. The contents of intracellular cholesteryl esters were detected by enzyme-fluorescence. RESULTS: The mRNA and protein expressions of ACAT1 were significantly up-regulated in positive control cells compared those in negative control cells and further upregulated by C.pn infection in a time-dependent and concentration-dependent manner (all P < 0.05). There were significantly increases in the accumulation of lipid droplets and the ratio of cholesteryl ester to total cholesterol in positive control cells as compared with negative control cells and these were further aggravated by C.pn (at the concentrations of 5 x 10(5) and 1 x 10(6) IFU for 48 h) and C.pn infection induced increases in the accumulation of lipid droplets and the ratio of cholesteryl ester to total cholesterol could be significantly attenuated by ACAT inhibitor 58-035 (all P < 0.05). CONCLUSION: Chlamydia pneumoniae induces THP-1-derived foam cell formation by up-regulating the expression of ACAT1.

[Ghrelin down-regulates ACAT-1 in THP-1 derived foam cells via growth hormone secretagogue receptor-dependent pathway].

OBJECTIVE: To investigate the effects of Ghrelin on the expression of acyl coenzyme A:cholesterol acyltransferases-1 (ACAT-1) in THP-1 derived foam cells. METHODS: The human monocytic leukemia cell line (THP-1) was chosen in our study. The differentiation of THP-1 cells into macrophages was induced by phorbol 12-myristate 13-acetate. Macrophages were then incubated with oxidized LDL (ox-LDL) to generate foam cells. Ghrelin and [D-Lys3]-GHRP-6, the special antagonist of growth hormone secretagogue receptor (GHS-R), were treated during foam cells formation. The ACAT-1 protein and mRNA levels were detected by Western blot and RT-PCR. The effect of variance of cholesterol content was measured by zymochemistry via-fluorospectrophotometer. RESULTS: Ghrelin reduced the content of cholesterol ester in foam cells obviously. ACAT-1 protein and mRNA levels were also decreased. The antagonist of GHS-R inhibited the effects of Ghrelin on ACAT-1 expression in dose-dependent manner. The ACAT-1 mRNA levels of the GHS-R specific antagonist groups (10(-5), 5 x 10(-5), 10(-4) mol/L) were 1.14 +/- 0.04, 1.58 +/- 0.03, 2.40 +/- 0.16, significantly higher than that of the Ghrelin group (0.89 +/- 0.05). And the protein expressions were 1.25 +/- 0.09, 1.77 +/- 0.11, 2.30 +/- 0.09, also higher than that of the Ghrelin group (0.86 +/- 0.08). CONCLUSIONS: Ghrelin might interfere atherosclerosis by down-regulating the expression of ACAT-1 via GHS-R pathway.

Chlamydia pneumoniae disturbs cholesterol homeostasis in human THP-1 macrophages via JNK-PPARγ dependent signal transduction pathways.

Chlamydia pneumoniae (C. pneumoniae) induces macrophage-derived foam cell formation, a hallmark of early atherosclerosis, in the presence of low density lipoprotein (LDL). However, its mechanisms have yet to be elucidated. In this study we examined the effects of live, heat-killed and UV-inactivated C. pneumoniae on cholesterol metabolism in THP-1-derived macrophages and the role of c-Jun NH(2) terminal kinase (JNK), which may participate in the C. pneumoniae-induced disruption of intracellular cholesterol homeostasis. We investigated whether SP600125, a special JNK inhibitor, affects the expression of peroxisome proliferator-activated receptor gamma (PPARγ), and also its downstream target genes Acyl-CoA cholesterol acyltransferase-1 (ACAT1), ATP-binding cassette transporter A1 and G1 (ABCA1/G1) in human THP-1 macrophages infected with C. pneumoniae. In this paper we found that both live and inactivated C. pneumoniae infection induce intracellular cholesterol accumulation and foam cell formation. C. pneumoniae infection increased the expression of ACAT1 and decreased the expression of ABCA1/G1, all of which facilitated cholesterol accumulation and promoted macrophage-derived foam cell formation. However, these responses were attenuated by SP600125 in a dose-dependent manner. These results demonstrate for the first time that both live and inactivated C. pneumoniae infections disturb cholesterol homeostasis in human THP-1 macrophages and C. pneumoniae infection disturbs cholesterol homeostasis via JNK-PPARγ dependent signal transduction pathways.

Interleukin-10 inhibits the down-regulation of ATP binding cassette transporter A1 by tumour necrosis factor-alpha in THP-1 macrophage-derived foam cells.

It is suggested that cholesterol efflux mediated by ATP binding cassette transporter A1 (ABCA1) plays an important role in anti-atherogenesis. However, the effects of inflammatory cytokines on ABCA1 expression and cholesterol accumulation in foam cells are little known. This study investigates the effects of tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) on ABCA1 expression and cholesterol content in THP-1 macrophage-derived foam cells. ABCA1mRNA and protein levels were determined by RT-PCR and Western blot, respectively. The total cholesterol content in THP-1 macrophage-derived foam cells was detected by the zymochemistry method. Results revealed that TNF-alpha could increase cholesterol content by down-regulating ABCA1 expression in a time-dependent manner in THP-1 macrophage-derived foam cells, which may contribute to its pro-atherosclerotic effect. In addition IL-10 time-dependently decreased cholesterol accumulation by up-regulating ABCA1 expression and inhibited the down-regulation of ABCA1 by TNF-alpha in THP-1 macrophage-derived foam cells, which may be one of the mechanisms of IL-10 contributing to its anti-atherosclerotic action.